Sudden unexpected death in epilepsy (SUDEP) is characterized by sudden unexpected, nontraumatic, and nondrowning deaths in epileptic patients. SUDEP is the most common cause of mortality in individuals with epilepsy. There are reports of the incidence of SUDEP being as high as 1 in 200 in patients with severe epilepsy. However, this is likely to be an underestimate as the actual number of SUDEP cases is thought to be underreported. Among the candidate mechanisms for SUDEP, cardiac etiologies are a strong possibility. Sudden cardiac death resulting from cardiac arrhythmia such as ventricular tachycardia and fibrillation is associated with alterations in cardiac ion channels responsible for the regulation of the heart rate and rhythm. These types of changes also occur in association with cardiac pathology, which is considered a risk factor for arrhythmia. Imbalance in the autonomic nervous system, specifically sympathetic nervous system activity is considered an important player in the development of ventricular tachyarrhythmias. A number of clinical studies support the concept that autonomic alterations exist in individuals with epilepsy and that this may be more pronounced in the group with SUDEP. Thus, cardiac arrhythmogenic events, possibly related to autonomic dysregulation and cardiac ion channel remodeling represent a strong candidate mechanism underlying SUDEP. In the studies outlined we will utilize the pilocarpine model of acquired epilepsy that recapitulates a number of the features of chronic epilepsy in humans, including unprovoked seizures, tachycardia, and an increased risk of sudden death. Our pilot studies in these animals reveal that there is cardiac arrhythmogenesis and ion channel remodeling. Through an interdisciplinary collaboration between investigators from the fields of epilepsy and cardiac electrophysiology we will test the hypothesis that epilepsy results in cardiac molecular remodeling and an associated propensity for arrhythmogenesis. We propose that aberrant autonomic nervous system function is a candidate mediator for these changes. PUBLIC HEALTH RELEVANCE: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of mortality in epilepsy. The mechanisms underlying SUDEP are unknown and cardiac etiologies are a strong possibility. We have preliminary data implicating abnormal cardiac function in an animal model of epilepsy and propose to use this model to further study this abnormality and elucidate therapies to reverse these changes.